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Objective: To examine the extent to which geometric parameters derived from dual-energy x-ray absorptiometry (DXA) scans in the UK Biobank study are related to hip osteoarthritis (HOA) independently of sex, age and body size., Design: Femoral neck width (FNW), diameter of the femoral head (DFH) and hip axis length (HAL) were derived automatically from left hip DXA scans in UK Biobank using outline points placed around the hip by a machine-learning program. Correlations were calculated between geometric parameters, age, height, and weight. Logistic regression was used to examine the relationship of geometric parameters with radiographic HOA, hospital diagnosed HOA (HESOA), and Cox proportional hazards model to evaluate the relationship with total hip replacement (THR). Analyses were adjusted for sex, age, height, weight, and geometric parameters., Results: The study consisted of 40,312 participants. In age and sex-adjusted analyses, FNW, HAL and DFH were related to increased risk of radiographic HOA. In a model adjusted for age, sex, height, weight and other geometric parameters, both FNW and HAL retained independent relationships with radiographic HOA [FNW: odds ratios 2.38 (2.18-2.59), HAL: 1.25 (1.15-1.36)], while DFH was now protective [0.55 (0.50-0.61)]. Only FNW was independently related to HESOA [2.20 (1.80-2.68)] and THR [hazard ratios 2.51 (1.89-3.32)]., Conclusion: Greater FNW and HAL were independently related to an increased risk of radiographic HOA, whereas greater DFH appeared to be protective. Greater FNW was independently associated with HESOA and THR. These results suggest that DXA-derived geometric parameters, particularly FNW, could help determine HOA and THR risk., Competing Interests: Declaration of Competing Interest TC & CL have a patent image processing apparatus and method for fitting a deformable shape model to an image using random forest regression voting. This is licensed with royalties to Optasia Medical. NH reports consultancy fees and honoraria from UCB, Amgen, Kyowa Kirin, Thornton Ross, Consilient., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As muscle strength and function decline with age the optimal high-impact physical activity (PA) required for bone remodelling is rarely achievable in older adults. This study aimed to explore the activity profiles of community-dwelling older men and women and to assess the relationship between individual PA profiles and lower limb bone parameters. Participants from the Hertfordshire Cohort Study wore triaxial accelerometers for 7 days and counts of low (0.5-1.0 g), medium (1.0-1.5 g), and high (> 1.5 g) vertical-impact activity were calculated. Two years later, participants underwent a pQCT scan of the tibia (4% and 38% sites) to obtain measures of bone mineral density and bone geometry. Linear regression was used to quantify associations between bone and PA loading profiles adjusting for age, sex, loading category, and BMI. Results are presented as β [95% confidence interval]. Bone and PA data were available for 82 participants. The mean (SD) age at follow-up was 81.4(2.7) years, 41.5% (n = 34) were women. The median low-impact PA count was 5281 (Inter-quartile range (IQR) 2516-12,977), compared with a median of only 189 (IQR 54-593) in medium, and 39 (IQR 9-105) in high-impact counts. Positive associations between high-impact PA and cortical area (mm 2 ), polar SSI (mm 3 ), and total area (mm 2 ) at the 38% slice (6.21 [0.88, 11.54]; 61.94 [25.73, 98.14]; 10.09 [3.18, 16.99], respectively). No significant associations were found at distal tibia. These data suggest that maintaining high (> 1.5 g)-impact activity is difficult for older adults to achieve; however, even small amounts of high-impact PA are positively associated with selected cortical bone parameters 2 years later., (© 2022. The Author(s).)

Purpose of Review: This paper reviews how bone genetics has contributed to our understanding of the pathogenesis of osteoarthritis. As well as identifying specific genetic mechanisms involved in osteoporosis which also contribute to osteoarthritis, we review whether bone mineral density (BMD) plays a causal role in OA development., Recent Findings: We examined whether those genetically predisposed to elevated BMD are at increased risk of developing OA, using our high bone mass (HBM) cohort. HBM individuals were found to have a greater prevalence of OA compared with family controls and greater development of radiographic features of OA over 8 years, with predominantly osteophytic OA. Initial Mendelian randomisation analysis provided additional support for a causal effect of increased BMD on increased OA risk. In contrast, more recent investigation estimates this relationship to be bi-directional. However, both these findings could be explained instead by shared biological pathways. Pathways which contribute to BMD appear to play an important role in OA development, likely reflecting shared common mechanisms as opposed to a causal effect of raised BMD on OA. Studies in HBM individuals suggest this reflects an important role of mechanisms involved in bone formation in OA development; however further work is required to establish whether the same applies to more common forms of OA within the general population.

Objective: High bone mass (HBM) is associated with an increased prevalence of radiographic knee OA (kOA), characterized by osteophytosis. We aimed to determine if progression of radiographic kOA, and its sub-phenotypes, is increased in HBM and whether observed changes are clinically relevant., Design: A cohort with and without HBM (L1 and/or total hip bone mineral density Z-score≥+3.2) had knee radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Medial/lateral tibial/femoral osteophyte and medial/lateral joint space narrowing (JSN) grades were summed and Δosteophytes, ΔJSN derived. Pain, function and stiffness were quantified using the WOMAC questionnaire. Associations between HBM status and sub-phenotype progression were determined using multivariable linear/poisson regression, adjusting for age, sex, height, baseline sub-phenotype grade, menopause, education and total body fat mass (TBFM). Generalized estimating equations accounted for individual-level clustering., Results: 169 individuals had repeated radiographs, providing 330 knee images; 63% had HBM, 73% were female, mean (SD) age was 58 (12) years. Whilst HBM was not clearly associated with overall Kellgren-Lawrence measured progression (RR = 1.55 [0.56.4.32]), HBM was positively associated with both Δosteophytes and ΔJSN individually (adjusted mean differences between individuals with and without HBM 0.45 [0.01.0.89] and 0.15 [0.01.0.29], respectively). HBM individuals had higher WOMAC knee pain scores (β = 7.42 [1.17.13.66]), largely explained by adjustment for osteophyte score (58% attenuated) rather than JSN (30% attenuated) or TBFM (16% attenuated). The same pattern was observed for symptomatic stiffness and functional limitation., Conclusions: HBM is associated with osteophyte progression, which appears to contribute to increased reported pain, stiffness and functional loss., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

We compared bone outcomes in adolescents with breech and cephalic presentation. Tibia bone mineral content, density, periosteal circumference, and cross-sectional moment of inertia were lower in breech presentation, and females with breech presentation had lower hip CSA. These findings suggest that prenatal loading may exert long-lasting influences on skeletal development., Introduction: Breech position during pregnancy is associated with reduced range of fetal movement, and with lower limb joint stresses. Breech presentation at birth is associated with lower neonatal bone mineral content (BMC) and area, but it is unknown whether these associations persist into later life., Methods: We examined associations between presentation at onset of labor, and tibia and hip bone outcomes at age 17 years in 1971 participants (1062 females) from a UK prospective birth cohort that recruited > 15,000 pregnant women in 1991-1992. Cortical BMC, cross-sectional area (CSA) and bone mineral density (BMD), periosteal circumference, and cross-sectional moment of inertia (CSMI) were measured by peripheral quantitative computed tomography (pQCT) at 50% tibia length. Total hip BMC, bone area, BMD, and CSMI were measured by dual-energy X-ray absorptiometry (DXA)., Results: In models adjusted for sex, age, maternal education, smoking, parity, and age, singleton/multiple births, breech presentation (n = 102) was associated with lower tibial cortical BMC (- 0.14SD, 95% CI - 0.29 to 0.00), CSA (- 0.12SD, - 0.26 to 0.02), BMD (- 0.16SD, - 0.31 to - 0.01), periosteal circumference (- 0.14SD, - 0.27 to - 0.01), and CSMI (- 0.11SD, - 0.24 to 0.01). In females only, breech presentation was associated with lower hip CSA (- 0.24SD, - 0.43 to 0.00) but not with other hip outcomes. Additional adjustment for potential mediators (delivery method, birthweight, gestational age, childhood motor competence and adolescent height and body composition) did not substantially affect associations with either tibia or hip outcomes., Conclusions: These findings suggest that prenatal skeletal loading may exert long-lasting influences on skeletal size and strength but require replication.

In a population-based sample of British women aged over 70 years old, lean mass and peak lower limb muscle force were both independently associated with hip strength and fracture risk indices, thereby suggesting a potential benefit of promoting leg muscle strengthening exercise for the prevention of hip fractures in postmenopausal women., Introduction: To investigate cross-sectional associations of lean mass and physical performance, including lower limb muscle function, with hip strength, geometry and fracture risk indices (FRIs) in postmenopausal women., Methods: Data were from the Cohort of Skeletal Health in Bristol and Avon. Total hip (TH) and femoral neck (FN) bone mineral density (BMD), hip geometry and total body lean mass (TBLM) were assessed by dual x-ray absorptiometry (DXA). Finite element analysis of hip DXA was used to derive FN, intertrochanteric and subtrochanteric FRIs. Grip strength, gait speed and chair rise time were measured objectively. Lower limb peak muscle force and muscle power were assessed by jumping mechanography., Results: In total, 241 women were included (age = 76.4; SD = 2.6 years). After adjustment for age, height, weight/fat mass and comorbidities, TBLM was positively associated with hip BMD (β TH BMD  = 0.36, P ≤ 0.001; β FN BMD  = 0.26, P = 0.01) and cross-section moment of inertia (0.24, P ≤ 0.001) and inversely associated with FN FRI (- 0.21, P = 0.03) and intertrochanteric FRI (- 0.11, P = 0.05) (estimates represent SD difference in bone measures per SD difference in TBLM). Lower limb peak muscle force was positively associated with hip BMD (β TH BMD  = 0.28, P ≤ 0.001; β FN BMD  = 0.23, P = 0.008) and inversely associated with FN FRI (- 0.17, P = 0.04) and subtrochanteric FRI (- 0.18, P = 0.04). Associations of grip strength, gait speed, chair rise time and peak muscle power with hip parameters were close to the null., Conclusions: Lean mass and lower limb peak muscle force were associated with hip BMD and geometrical FRIs in postmenopausal women. Leg muscle strengthening exercises may therefore help prevent hip fractures in older women.

We examined bone density in older athletes and controls. Sprinters had greater hip and spine bone density than endurance athletes and controls, whereas values were similar in the latter two groups. These results could not be explained by differences in impact, muscle size or power between sprint and endurance athletes., Purpose: We examined the relationship between prolonged participation in regular sprint or endurance running and skeletal health at key clinical sites in older age, and the factors responsible for any associations which we observed., Methods: We recruited 38 master sprint runners (28 males, 10 females, mean age 71 ± 7 years), 149 master endurance runners (111 males, 38 females, mean age 70 ± 6 years) and 59 non-athletic controls (29 males, 30 females, mean age 74 ± 5 years). Dual X-ray absorptiometry was used to assess hip and spine bone mineral density (BMD), body composition (lean and fat mass), whilst jump power was assessed with jumping mechanography. In athletes, vertical impacts were recorded over 7 days from a waist-worn accelerometer, and details of starting age, age-graded performance and training hours were recorded., Results: In ANOVA models adjusted for sex, age, height, body composition, and jump power, sprinter hip BMD was 10 and 14% greater than that of endurance runners and controls respectively. Sprinter spine BMD was also greater than that of both endurance runners and controls. There were no differences in hip or spine BMD between endurance runners and controls. Stepwise regression showed only discipline (sprint/endurance), sex, and age as predictors of athlete spine BMD, whilst these variables and starting age were predictive of hip BMD., Conclusions: Regular running is associated with greater BMD at the fracture-prone hip and spine sites in master sprinters but not endurance runners. These benefits cannot be explained by indicators of mechanical loading measured in this study including vertical impacts, body composition or muscular output.

This study assessed the effect of accelerometry-measured higher impacts resulting from habitual weight-bearing activity on lower limb bone strength in older women. Despite higher impacts being experienced rarely in this population-based cohort, positive associations were observed between higher vertical impacts and lower limb bone size and strength., Introduction: We investigated whether the benefit of habitual weight-bearing physical activity (PA) for lower limb bone strength in older women is explained by exposure to higher impacts, as previously suggested by observations in younger individuals., Methods: Four hundred and eight women from the Cohort for Skeletal Health in Bristol and Avon (COSHIBA), mean 76.8 years, wore tri-axial accelerometers at the waist for a mean of 5.4 days. Y-axis peaks were categorised, using previously identified cutoffs, as low (0.5-1.0 g), medium (1.0-1.5 g), and higher (≥1.5 g) impacts. Mid and distal peripheral quantitative computed tomography scans of the tibia and radius were performed, as were hip and lumbar spine Dual X-ray Absorptiometry (DXA) scans. Regressions between (log transformed) number of low, medium and high impacts, and bone outcomes were adjusted for artefact error grade, age, height, fat and lean mass and impacts in other bands., Results: Eight thousand eight hundred and nine (4047, 16,882) low impacts were observed during the measurement week, 345 (99, 764) medium impacts and 42 (17, 106) higher impacts (median with 25th and 75th quartiles). Higher vertical impacts were positively associated with lower limb bone strength as reflected by cross-sectional moment of inertia (CSMI) of the tibia [0.042 (0.012, 0.072) p = 0.01] and hip [0.067 (0.001, 0.133) p = 0.045] (beta coefficients show standard deviations change per doubling in impacts, with 95 % confidence interval). Higher impacts were positively associated with tibial periosteal circumference (PC) [0.015 (0.003, 0.027) p = 0.02], but unrelated to hip BMD. Equivalent positive associations were not seen for low or medium impacts., Conclusions: Despite their rarity, habitual levels of higher impacts were positively associated with lower limb bone size and strength, whereas equivalent relationships were not seen for low or medium impacts.

Summary: This qualitative study explored the acceptability of high-impact physical activity for increasing bone strength in later life. Thematic analysis established the barriers and facilitators to this physical activity. They prioritised joint over skeletal health, of which they had little concept. Interventions need to clearly communicate the rationale and benefits., Introduction: The aim of this study was to explore the acceptability of doing high-impact physical activity in later life., Methods: This qualitative study was embedded within a large-scale observational study and was designed to address specific objectives and feed into a subsequent intervention. Five focus groups with physically active men and women (over 50 years) were used to develop an interview topic guide to explore the acceptability of high-impact physical activity in older men and women (over 65 years) in South West England. A total of 28 semi-structured interviews with 31 participants were then conducted and transcripts analysed thematically., Results: Three main barriers emerged: conceptualising bone, damage to joints and falling/safety concerns. Two main facilitators were also identified: the need to understand clear tangible benefits and incorporation of activity into everyday habits. Older adults were interested how high-impact physical activity would help to maintain their mobility, independence or social relationships. Some participants wanted tangible feedback from accelerometers, health care professionals and/or bone scans in order to develop a more intimate knowledge of their bone health., Conclusions: Interventions incorporating high-impact physical activity for older adults need to communicate how this activity can impact more broadly on health and lives; that physical activity will be safe, beneficial and not damaging to their joints will need to be clearly conveyed. Ways in which high-impact physical activity can be habitualised into everyday activities, be fun and interactive may help facilitate longer term adoption.

Objective: Epidemiological studies have shown an association between increased bone mineral density (BMD) and osteoarthritis (OA), but whether this represents cause or effect remains unclear. In this study, we used a novel approach to investigate this question, determining whether individuals with High Bone Mass (HBM) have a higher prevalence of radiographic hip OA compared with controls., Design: HBM cases came from the UK-based HBM study: HBM was defined by BMD Z-score. Unaffected relatives of index cases were recruited as family controls. Age-stratified random sampling was used to select further population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs were pooled and assessed by a single observer blinded to case-control status. Analyses used logistic regression, adjusted for age, gender and body mass index (BMI)., Results: 530 HBM hips in 272 cases (mean age 62.9 years, 74% female) and 1702 control hips in 863 controls (mean age 64.8 years, 84% female) were analysed. The prevalence of radiographic OA, defined as Croft score ≥3, was higher in cases compared with controls (20.0% vs 13.6%), with adjusted odds ratio (OR) [95% CI] 1.52 [1.09, 2.11], P = 0.013. Osteophytes (OR 2.12 [1.61, 2.79], P < 0.001) and subchondral sclerosis (OR 2.78 [1.49, 5.18], P = 0.001) were more prevalent in cases. However, no difference in the prevalence of joint space narrowing (JSN) was seen (OR 0.97 [0.72, 1.33], P = 0.869)., Conclusions: An increased prevalence of radiographic hip OA and osteophytosis was observed in HBM cases compared with controls, in keeping with a positive association between HBM and OA and suggesting that OA in HBM has a hypertrophic phenotype., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Context: Intracellular fat within muscle and visceral tissue has been suggested to adversely influence bone development., Objective: The aim of the study was to evaluate associations between im fat, as reflected by muscle density as measured by peripheral quantitative computed tomography, and cortical bone parameters in young adults., Design/setting/participants: We conducted a cross-sectional analysis of 1703 males and 2243 females aged 17.8 years from the Avon Longitudinal Study of Parents and Children., Outcome Measures: We measured cortical bone parameters from midtibial peripheral quantitative computed tomography scans., Results: Muscle density (inversely related to im fat) was inversely associated with periosteal circumference (PC) (beta = -0.07 [95% confidence interval (CI), -0.1, -0.04]), cortical bone mineral density (BMDC) (beta = -0.21 [95% CI, -0.26, -0.17]), and cortical thickness (CT) (beta = -0.37 [95% CI, -0.42, -0.33]) (males and females combined, adjusted for age, height, gender, and muscle cross-sectional area). In contrast, sc fat area was positively associated with PC (beta = 0.10 [95% CI, 0.07, 0.12]), but no association was seen with BMDC or CT. To examine the role of candidate intermediary metabolic pathways, analyses were repeated after adjustment for insulin, C-reactive protein, and β-C-telopeptides of type I collagen. Whereas similar associations were observed after adjustment for insulin and C-reactive protein, the association between muscle density and BMDC was partially attenuated by adjustment for β-C-telopeptides of type I collagen (beta = -0.14 [95% CI, -0.20, -0.08])., Conclusion: Although im and sc fat were both positively associated with cortical bone mass, the nature of these relationships differed in that im fat was predominantly associated with CT and BMDC, whereas sc fat was mainly associated with PC. These relationships were largely independent of candidate metabolic pathways, such as altered bone resorption, insulin resistance, or inflammation.

Unlabelled: In exploring relationships between vitamin D status in childhood and cortical bone, little relationship was observed with plasma concentrations of 25-hydroxyvitamin-D(2) [25(OH)D(2)], whereas 25-hydroxyvitamin-D(3) [25(OH)D(3)] was positively related to cortical bone mineral content (BMC(C)) and cortical thickness, suggesting D(3) exerts a beneficial effect on cortical bone development in contrast to D(2)., Introduction: The study is aimed to determine whether vitamin D status in childhood is related to cortical bone development by examining prospective relationships between plasma concentrations of 25(OH)D(2) and 25(OH)D(3) at 7.6, 9.9 or 11.8 years and peripheral quantitative computed tomography (pQCT) measurements of the mid-tibia at age 15.5 years, in children from the Avon Longitudinal Study of Parents and Children., Methods: Relationships between vitamin D status and pQCT outcomes were analysed by bootstrap linear regression, adjusted for age, sex, body composition, socioeconomic position and physical activity, in 2,247 subjects in whom all covariates were available. 25(OH)D(3) was also adjusted for season and 25(OH)D(2), and 25(OH)D(2) for 25(OH)D(3)., Results: 25(OH)D(3) was positively related to BMC(C) [0.066(0.009,0.122), P = 0.02], whereas no association was seen with 25(OH)D(2) [-0.008(-0.044,0.027), P = 0.7] [beta (with 95% CI) represents SD changes per doubling of vitamin D], P = 0.03 for difference in associations of 25(OH)D(2) and 25(OH)D(3) with BMC(C). There were also differences in associations with cortical geometry, since 25(OH)D(3) was positively related to cortical thickness [0.11(0.04, 0.19), P = 0.002], whereas no association was seen with 25(OH)D(2) [-0.04(-0.08,0.009), P = 0.1], P = 0.0005 for difference. These relationships translated into differences in biomechanical strength as reflected by buckling ratio, which was positively related to 25(OH)D(2) [0.06(0.01,0.11), P = 0.02] indicating less resistance to buckling, but inversely related to 25(OH)D(3) [-0.1(-0.19,-0.02), P = 0.03], P = 0.001 for difference., Conclusions: In contrast to 25(OH)D(2), 25(OH)D(3) was positively related to subsequent cortical bone mass and predicted strength. In vitamin D-deficient children in whom supplementation is being considered, our results suggest that D(3) should be used in preference to D(2).

Summary: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder., Introduction: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia., Methods: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex., Results: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m(2), p < 0.001)., Conclusion: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Unlabelled: We investigated an intrauterine influence of maternal smoking during pregnancy on childhood bone mass. Daughters, but not sons, of mothers who smoked had higher bone mass at age 10years. This appears to be due to familial factors related to parental smoking influencing increased offspring adiposity rather than a direct intrauterine effect., Introduction: Neonatal studies have demonstrated an adverse relationship between maternal smoking in pregnancy and foetal bone mineral accrual. We aimed to investigate an intrauterine influence of maternal smoking during pregnancy on offspring bone mass at mean age 9.9 years., Methods: We compared associations of maternal and paternal smoking in pregnancy with offspring total body less head (TBLH) and spine bone mineral content (BMC), bone area (BA), bone mineral density (BMD) and area-adjusted BMC (ABMC) in 7,121 children in the Avon Longitudinal Study of Parents and Children., Results: Maternal smoking in any trimester was associated with increased TBLH BMC, BA and BMD in girls (mean difference [95% CI] (sex-specific SD scores), 0.13 [0.05-0.22], 0.13 [0.04-0.21], 0.13 [0.04-0.22], respectively) but not boys (0.01 [-0.07-0.09], 0.00 [-0.08-0.08], 0.04 [-0.05-0.12]), and also with spine BMC, BA and BMD in girls (0.13 [0.03-0.23], 0.12 [0.03-0.22], 0.10 [0.00-0.21]) but not boys (0.03 [-0.06-0.12], 0.00 [-0.09-0.09], 0.05 [-0.04-0.14]), but not with ABMC. Paternal smoking associations were similar, with no statistical evidence for a difference between maternal and paternal effects. Maternal associations increased on adjustment for offspring birth weight and gestational age, but attenuated to the null after adjustment for current height and weight., Conclusions: We found little evidence that maternal smoking was related to bone mass in boys. In girls, maternal smoking associations were similar to those of paternal smoking, suggesting that these were attributable to shared familial characteristics, not intrauterine mechanisms.

Context: Several single-nucleotide polymorphisms (SNPs) have been reliably associated with areal bone mineral density (aBMD) in genome-wide association studies of mostly older subjects., Objective: We aimed to test those SNPs for an association with peripheral quantitative computed tomography (pQCT) bone measures in two young cohorts., Design and Study Participants: We genotyped nine SNPs from the most promising aBMD candidates in a cohort of 15-yr-olds [in the Avon Longitudinal Study of Parents and Children (ALSPAC)] and carried out association analysis with several tibial pQCT measures to determine whether these candidates were important during adolescent growth and which particular skeletal parameters each of the candidates were acting upon. We also carried out a metaanalysis of the SNPs for association with cortical bone mineral density (BMDC) in ALSPAC and a similar male-only study (Gothenburg Osteoporosis and Obesity Determinants)., Results: In the ALSPAC cohort, we found a significant association between RANK SNP (rs3018362) and BMDC but not any of the other pQCT bone measures. In the metaanalysis, we found the OPG SNP (rs4355801) and the RANK SNP (rs3018362) to be significantly associated with BMDC. We also found suggestive evidence of an association between the MARK3 SNP (rs2010281) and BMDC but with a direction of effect opposite to that previously reported., Conclusion: The association of genes from the RANK/RANKL/OPG pathway and BMDC provides new insight into how this system might affect the skeleton, confirming it to be associated with volumetric cortical bone density but observing no relationship with bone size.

Context: Whether the action of estrogen in skeletal development depends on estrogen receptor alpha as encoded by the ESR1 gene is unknown., Objectives: The aim of this study was to establish whether the gain in area-adjusted bone mineral content (ABMC) in girls occurs in late puberty and to examine whether the magnitude of this gain is related to ESR1 polymorphisms., Design: We conducted a cross-sectional analysis., Setting: The study involved the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based prospective study., Participants: Participants included 3097 11-yr-olds with DNA samples, dual x-ray absorptiometry measurements, and pubertal stage information., Outcomes: Outcome measures included separate prespecified analyses in boys and girls of the relationship between ABMC derived from total body dual x-ray absorptiometry scans and Tanner stage and of the interaction between ABMC, Tanner stage, and ESR1 polymorphisms., Results: Total body less head and spinal ABMC were higher in girls in Tanner stages 4 and 5, compared with those in Tanner stages 1, 2, and 3. In contrast, height increased throughout puberty. No differences were observed in ABMC according to Tanner stage in boys. For rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms, differences in spinal ABMC in late puberty were 2-fold greater in girls who were homozygous for the C and G alleles, respectively (P = 0.001). For rs7757956, the difference in total body less head ABMC in late puberty was 50% less in individuals homozygous or heterozygous for the A allele (P = 0.006)., Conclusions: Gains in ABMC in late pubertal girls are strongly associated with ESR1 polymorphisms, suggesting that estrogen contributes to this process via an estrogen receptor alpha-dependent pathway.

Objective: The objective of this article was to systematically review all published studies that investigated the association between bone density and fractures in children., Design: Potentially relevant articles were identified by searching electronic databases. Duplicates were removed, abstracts were inspected, and relevant articles were obtained. Studies were included in the systematic review if participants were <16.0 years old, were healthy, had extractable data on bone mass, and had fractures as the outcome., Results: Ten case-control studies were identified. No prospective studies were found. There was no evidence of heterogeneity between studies or of funnel-plot asymmetry. Eight of the studies were included in the meta-analysis, because they presented results as means and standard deviations of bone density in cases and controls. The pooled standardized mean difference for bone mass in children with and without fractures, from a fixed-effects model, was -0.32 (95% confidence interval: -0.43 to -0.21)., Conclusions: Evidence for an association between bone density and fractures in children is limited. The results from this meta-analysis suggest that there is an association between low bone density and fractures in children. Although there was no evidence of heterogeneity or publication bias, this meta-analysis is based on case-control studies that are prone to bias. Large, well-conducted prospective cohort studies are required to confirm the association between bone density and fractures in children.

Evidence that birth weight is related to bone mass in later life suggests that the intrauterine environment programs the trajectory of subsequent bone development. To explore this hypothesis, we examined whether maternal diet in pregnancy, as assessed by the maternal food frequency questionnaire (FFQ) completed at 32 weeks gestation, is related to bone mass of the child, as measured by total body DXA carried out at age 9 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Diet records were linked to DXA scan results for the total body and spine sub-region and pooled between pre- and early pubertal boys and girls (n=4,451). Regression analysis was carried out between DXA values and dietary factors following adjustment for social and other confounding factors. Maternal magnesium intake was related to total body BMC (beta=4.9, 7.4-23.1; g) and BMD (beta=4.9, 2.5-7.3; g/cm2 x10(3)) (standardized regression coefficient with 95% confidence limits; P<0.001). An equivalent relationship was no longer observed after adjusting for the height of the child, to which magnesium intake was also related (beta=0.48, 0.20-0.77; cm; P=0.001). Maternal intake of potassium was related to spinal BMC (beta=1.8, 0.8-2.9; g) and BMD (beta=10.5, 4.9-16.0; g/cm2 x10(3)) (P=0.001), which was no longer observed after adjusting for the weight of the child, to which potassium intake was also related (beta=0.52, 0.16-0.88, P=0.005; kg). A significant association was also observed between maternal dietary folate intake and spinal BMC adjusted for bone area using a linear regression model (beta=0.55, 0.16-0.94; g; P=0.006), which persisted after adjusting for height and weight. Our observation that constituents of maternal diet are related to DXA measures at age 9 is consistent with the hypothesis that the trajectory of bone development in childhood is programmed by early life factors.

Although radiological studies suggest that Marfan syndrome is associated with osteopenia, investigations utilizing measurements of bone mass have yielded conflicting results. To address this question further, we measured bone mineral density (BMD) in 14 women with Marfan syndrome at the right hip and lumbar spine by dual energy X-ray absorptiometry (DXA). Results were compared with the age- and weight-matched reference population supplied by the DXA manufacturer, and with our own control population of normal women, the latter being matched for height, in addition to age and weight. We found that BMD was very similar in our Marfan women as compared with the two reference populations, at the lumbar spine and femoral neck, while trochanteric BMD was reduced. However, the relationship between an isolated reduction in trochanteric BMD and future fracture risk is unclear, and, on the basis of our results, we conclude that Marfan syndrome is not associated with a clinically significant increase in the risk of osteoporotic fracture.

1. We analysed the lumbar spine (L2-L4) and femoral neck bone mineral density results of Caucasian (n = 2232), Asian (Indian sub-continent) (n = 153) and Afro-Caribbean (n = 102) women referred for bone densitometry over a 30 month period. To assess the risk of osteoporosis, the results of Caucasian and Asian women were compared with those of a reference Caucasian population supplied by Lunar. 2. Subject characteristics were similar in all three groups, other than expected ethnic differences in stature and weight. We found that lumbar spine and femoral neck bone mineral density in Caucasians was lower than in Afro-Caribbeans, but higher than in Asians. Consistent with this, bone mineral density was also lower in Asians as compared with the reference Caucasian population, both at the lumbar spine and femoral neck. As a consequence, a higher proportion of Asian women were classified as being at increased risk of osteoporosis than Caucasian women. 3. Since ethnic differences in skeletal size might influence bone mineral density, we also obtained values for bone mineral content in Caucasian and Asian women that were corrected for projected skeletal area, and weight and years since menopause, using regression equations derived from the Caucasian study population. After this analysis, the difference in bone mineral content between Caucasians and Asians at the lumbar spine disappeared, while that at the femoral neck persisted. 4. We conclude that the assessment of risk of osteoporosis in Asian women by comparing bone mineral density with a reference Caucasian population may have limited validity because of the influence of skeletal size on such measurements.

Bone mineral density (BMD) was evaluated by dual energy x ray absorptiometry in 60 adults (33 males, 27 females; aged 50, range 23-76 years) who were growth hormone deficient from various causes for 10.4 (1-31) years. Adult patients who had acquired growth hormone deficiency before completion of puberty had significantly reduced mean (SEM) BMD compared with age matched healthy controls at the lumbar spine: 0.87 (0.09) v 1.20 (0.03) g/cm2, femoral neck: 0.81 (0.06) v 1.08 (0.04) g/cm2, and Ward's triangle: 0.68 (0.07) v 1.04 (0.05) g/cm2. These values were also reduced compared with those of patients who had received human growth hormone during puberty. Untreated growth hormone deficiency when present during puberty results in reduced adult bone density.

Objective Studies in neonates have demonstrated an adverse relationship between maternal smoking during pregnancy and fetal bone mineral accrual. We aimed to investigate an intrauterine influence of maternal smoking in pregnancy on offspring bone mass during childhood. Design Prospective birth cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC). Setting Mothers were resident in Avon, UK during pregnancy and had expected delivery dates between April 1991 and December 1992. Participants and Methods Our analysis included 7121 children attending a research clinic at mean age 9.9 years. We used multiple regression models to compare associations of maternal and paternal smoking at the time of pregnancy with measures of bone size and density in the children, since a greater maternal association would provide evidence of a direct intrauterine effect on the fetus. Multivariate multiple imputations were used to account for missing data. Main Outcome Measures DXA measured total body less head (TBLH) and spine bone mineral content (BMC), bone area (BA) and bone mineral density (BMD). Results Maternal smoking in any trimester of pregnancy was associated with increased TBLH BMC, BA and BMD in girls (mean difference (95% CI) (using sex-specific SD scores): 0.13 (0.05 to 0.22), 0.13 (0.04 to 0.21) and 0.13 (0.04 to 0.22), respectively) but not in boys (0.01 (−0.07 to 0.09), 0.00 (−0.08 to 0.08), 0.04 (−0.05 to 0.12)) in confounder-adjusted models. It was also associated with spine BMC, BA and BMD in girls (0.13 (0.03 to 0.23), 0.12 (0.03 to 0.22), 0.10 (0.00 to 0.21)) but not in boys (0.03 (−0.06 to 0.12), 0.00 (−0.09 to 0.09), 0.05 (−0.04 to 0.14)). Paternal smoking associations were similar, with no statistical evidence for a difference between maternal and paternal associations (all p values >0.15). Maternal associations increased on adjustment for offspring birth weight and gestational age but attenuated to the null on adjustment for the child's height and weight at age 9 years. Further investigation indicated that these relationships were driven mainly by offspring weight rather than height. Conclusions There was little evidence of a relationship between maternal smoking during pregnancy and bone mass in boys. Our parental comparisons and multivariable analyses suggested that the positive associations between maternal smoking and bone mass in girls were likely to be attributable to shared familial characteristics related to offspring adiposity rather than an intrauterine mechanism. [ABSTRACT FROM PUBLISHER]